HIV-1-infected intravenous drug abusers and homosexuals develop thrombocytopenia (HIV-1-ITP) which is particularly severe in drug abusers. Although originally thought to be a disorder of immune peripheral destruction, there is now abundant evidence for impaired megakaryocytopoiesis (Mkp) and platelet production playing a major role, particularly in patients with more severe disease. We have discovered that high affinity anti-platelet GPIIIa 49-66 is sequestered within circulating immune complexes and that this anti- platelet Ab is capable of inhibiting Mkp in vitro with induction of apoptosis; and inducing platelet fragmentation in vitro in the absence of complement. We and most investigators have also noted that although MK and CD34+ progenitor cells are not infected with HIV-1, stromal cells can be infected. Activated stromal/endothelial cells secrete cytokines and support bone marrow angiogenesis. We therefore propose to study two mechanisms of impaired Mkp in HIV-1-ITP patients: 1) Autoimmunity: Role of anti-GPIIIa Ab in inhibiting Mkp and inducing non-complement dependent platelet fragmentation; 2) Infection of stromal cells: Role of HIV-1-infected stromal1endothelial cells in secretion of inhibitory Mkp cytokines and down-regulation of angiogenesis ligands VEGF, Ang-1 and their respective receptors VEGFr and Tie-2. These studies will provide useful information regarding the mechanism of impaired Mkp in HIV-1 infection which may contribute to the treatment and eradication of the thrombocyopenia.